Magnetic Resonance Imaging of Epilepsy in Multiple Sclerosis: A Case Control Study. Implications for Treatment Trials with 4-Aminopyridine

Abstract

A case-control study of epilepsy in multiple sclerosis (MS) is presented using magnetic resonance (MR) imaging to semiquantitatively assess cortical-subcortical lesion load. In this sample of 13 pairs of cases with MS and epilepsy and controls with MS without epilepsy we found statistically higher cumulated cortical-subcortical lesion loads in the cases than in the controls (Wilcoxon, P=0.036). Total lesion loads (cortical-subcortical plus deep white matter loads) did not differ significantly (P > 0.1) between cases and controls. The relative risk for seizures as determined by the odds ratio of a cortical-subcortical lesion load of ≥20 was. 8.8 (χ2 = 5.23, P 0.025), the odds ratio of a large (> 1 cm) cortico-subcortical lesion was 4.7 (χ2 = 4.9, P < 0.05), while the 2 MR criteria combined show an odds ratio of 19.2 (χ2 = 8.0, P < 0.005). We conclude that first, the presence of cortical-subcortical lesions in part accounts for the occurrence of seizures in MS patients; second, due to the substantial overlap of MR imaging scores between cases and controls the ultimate use of these MR imaging findings in the management of individual patients or in the organizations of trials should depend on the expected benefit of the treatment If the benefit is only moderate or not known a cautious approach with exclusion of cases showing a substantial cortical-subcortical lesion load on MR imaging seems appropriate in trials with drugs, like 4-aminopyridine, that lower the epileptic threshold.

Epileptic and non-epileptic seizures in multiple sclerosis

“…In a case-control study Truyen et al [83] found a significantly higher cortical-subcortical lesion load in MS patients suffering from epileptic seizures than in those without seizures. Deep white matter lesions did not differ between cases and controls.…”

“…In this context it has been argued that patients with a high load of cortical and subcortical lesions in MRI should be excluded from drug trials with remedies having a known potential to lower the seizure threshold [83]. While reasonable, this suggestion is based on the presumption that local factors and pharmacological effects are additive in their potential to cause seizures.…”

Gray matter damage in multiple sclerosis: Impact on clinical symptoms

“…Prevalence numbers of seizures in MS patients range from 0.5% to 8.3%, which is roughly three times higher than in the general population (Ghezzi et al, 1990;Moreau et al, 1998;Sokic et al, 2001;Nyquist et al, 2001;Gambardella et al, 2003;Poser and Brinar, 2003;Koch et al, 2008;Martinez-Juarez et al, 2009;Catenoix et al, 2011;Uribe-San-Martin et al, 2014). Most of the more dated research shows inconsistent results of the relation between (sub)cortical lesions and epileptic seizures (Ghezzi et al, 1990;Thompson et al, 1993;Truyen et al, 1996;Moreau et al, 1998;Sokic et al, 2001;Gambardella et al, 2003;Poser and Brinar, 2003;Uribe-San-Martin et al, 2014). Although tumefactive WM lesions with cortical compression were more likely to be related to seizure onset in these studies, the epileptogenic potential of smaller cortical lesions was less evident, and the electro-encephalography (EEG) defined onset zone frequently did not match lesion location (Ghezzi et al, 1990;Thompson et al, 1993;Truyen et al, 1996;Moreau et al, 1998;Sokic et al, 2001;Gambardella et al, 2003;Poser and Brinar, 2003;Uribe-San-Martin et al, 2014).…”

“…In the second half of the 20th century, it became clear that some clinical signs of MS, such as cognitive impairment (Benedict et al, 2004Morgen et al, 2006) and epileptic seizures (Ghezzi et al, 1990;Thompson et al, 1993;Truyen et al, 1996;Moreau et al, 1998;Sokic et al, 2001;Gambardella et al, 2003;Poser and Brinar, 2003;Uribe-San-Martin et al, 2014), could not be explained with WM pathology alone. Development of more advanced histopathological and magnetic resonance imaging (MRI) techniques subsequently led to more insights into GM pathology in MS.…”

Extensive cortical inflammation is associated with epilepsy in multiple sclerosis

“…Moreover, MS may present with epilepsy [6,7] and, in some cases, seizures may be the only manifestation of a MS relapse [8].Whether the two diseases occur accidentally,or MS non-specifically triggers a latent proneness to epilepsy, or MS is the actual causation of seizures is still debated [9]. Studies with conventional magnetic resonance (MR) sequences have suggested a possible correlation between the presence of cortical-juxtacortical MS lesions and epileptic seizures in MS [10,11].…”